Huntington's Disease (HD), is an hereditary neurodegenerative disorder which involves symptoms of dementia and dyskinesia. Neuropathologic studies of HD demonstrate a marked loss of striatal cholinergic and GABAergic neurons with sparing of the nigro-striatal dopaminergic pathway. We have developed a rat model for HD in which the selective degeneration of striatal intrinsic neurons is caused by direct injection of the conformationally restricted analogue of glutamate, kainic acid. The striatal kainate lesion produces neurochemical and histologic alterations in the nigro-striatal circuit that closely mimic those occurring in HD. Current studies involve a more detailed analysis of the neurochemical sequelae of the striatal degeneration including alterations in neurotransmitter receptors, disposition of neurotransmitters, and characteristics of the surviving dopaminergic terminals. We are examining the ability of cholino-mimetic ad GABA-mimetic agents to correct the neurotransmitter deficits in the lesion since effective drugs might be of therapeutic value in HD. The exact mechanism whereby kainate causes neuronal degeneration remain to be established. We are exploring the acute effects of kainate on neuronal metabolism and ion permeability in striatal slices incubated in vitro; the receptor mediating those effects is being characterized by means of binding studies with radioactive kainic acid. It is conceivable that the mechanism of neurotoxicity of kainate may shed light on the defect responsible for neuronal degeneration in HD.